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J Lipid Res. 2015 Mar;56(3):599-611. doi: 10.1194/jlr.M056069. Epub 2015 Jan 17.

A lipidomic screen of hyperglycemia-treated HRECs links 12/15-Lipoxygenase to microvascular dysfunction during diabetic retinopathy via NADPH oxidase.

Author information

1
Oral Biology and Anatomy, College of Dental Medicine, Medical College of Georgia, Georgia Regents University, Augusta, GA Ophthalmology and Culver Vision Discovery Institute, Medical College of Georgia, Georgia Regents University, Augusta, GA Department of Clinical Biochemistry, Faculty of Pharmacy, Mansoura University, Mansoura, Egypt.
2
Oral Biology and Anatomy, College of Dental Medicine, Medical College of Georgia, Georgia Regents University, Augusta, GA.
3
Department of Anesthesiology and Perioperative Medicine, Medical College of Georgia, Georgia Regents University, Augusta, GA.
4
Oral Biology and Anatomy, College of Dental Medicine, Medical College of Georgia, Georgia Regents University, Augusta, GA Ophthalmology and Culver Vision Discovery Institute, Medical College of Georgia, Georgia Regents University, Augusta, GA.
5
Oral Biology and Anatomy, College of Dental Medicine, Medical College of Georgia, Georgia Regents University, Augusta, GA Department of Anatomy, Faculty of Medicine,Mansoura University, Mansoura, Egypt.
6
Department of Physiology, Medical College of Georgia, Georgia Regents University, Augusta, GA.
7
Biomedical Science Program, Faculty of Science, Qatar University, Doha, Qatar.
8
Oral Biology and Anatomy, College of Dental Medicine, Medical College of Georgia, Georgia Regents University, Augusta, GA Cellular Biology and Anatomy, Medical College of Georgia, Georgia Regents University, Augusta, GA.
9
Oral Biology and Anatomy, College of Dental Medicine, Medical College of Georgia, Georgia Regents University, Augusta, GA Ophthalmology and Culver Vision Discovery Institute, Medical College of Georgia, Georgia Regents University, Augusta, GA Cellular Biology and Anatomy, Medical College of Georgia, Georgia Regents University, Augusta, GA.
10
Ophthalmology and Culver Vision Discovery Institute, Medical College of Georgia, Georgia Regents University, Augusta, GA Cellular Biology and Anatomy, Medical College of Georgia, Georgia Regents University, Augusta, GA.
11
Oral Biology and Anatomy, College of Dental Medicine, Medical College of Georgia, Georgia Regents University, Augusta, GA Ophthalmology and Culver Vision Discovery Institute, Medical College of Georgia, Georgia Regents University, Augusta, GA Department of Anatomy, Faculty of Medicine,Mansoura University, Mansoura, Egypt Cellular Biology and Anatomy, Medical College of Georgia, Georgia Regents University, Augusta, GA.

Abstract

Retinal hyperpermeability and subsequent macular edema is a cardinal feature of early diabetic retinopathy (DR). Here, we investigated the role of bioactive lipid metabolites, in particular 12/15-lipoxygenase (LOX)-derived metabolites, in this process. LC/MS lipidomic screen of human retinal endothelial cells (HRECs) demonstrated that 15-HETE was the only significantly increased metabolite (2.4 ± 0.4-fold, P = 0.0004) by high glucose (30 mM) treatment. In the presence of arachidonic acid, additional eicosanoids generated by 12/15-LOX, including 12- and 11-HETEs, were significantly increased. Fluorescein angiography and retinal albumin leakage showed a significant decrease in retinal hyperpermeability in streptozotocin-induced diabetic mice lacking 12/15-LOX compared with diabetic WT mice. Our previous studies demonstrated the potential role of NADPH oxidase in mediating the permeability effect of 12- and 15-HETEs, therefore we tested the impact of intraocular injection of 12-HETE in mice lacking the catalytic subunit of NADPH oxidase (NOX2). The permeability effect of 12-HETE was significantly reduced in NOX2(-/-) mice compared with the WT mice. In vitro experiments also showed that 15-HETE induced HREC migration and tube formation in a NOX-dependent manner. Taken together our data suggest that 12/15-LOX is implicated in DR via a NOX-dependent mechanism.

KEYWORDS:

12- and 15-HETEs; bioactive lipids; diabetic retinopathy; lipoxygenase; reduced nicotinamide adenine dinucleotide phosphate oxidase; retinal inflammation; retinal vascular leakage

PMID:
25598081
PMCID:
PMC4340307
DOI:
10.1194/jlr.M056069
[Indexed for MEDLINE]
Free PMC Article

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